The long-term goal of this research project is to understand the molecular and neural mechanisms governing energy homeostasis. Brain-derived neurotrophic factor (BDNF) plays crucial roles in energy balance, as mutations in the genes for BDNF and its receptor TrkB lead to obesity in both mice and humans;however, the precise role of BDNF in the regulation of body weight remains unknown. The organization and activity of hypothalamic neural circuits plays a critical role in the control of energy balance and BDNF is a potent regulator of neuronal development and synaptic plasticity. This application proposes to test the hypothesis that BDNF controls body weight by regulating the formation of neural circuits in the mediobasal hypothalamus that are known to control energy balance. Defects in axonal growth, synaptogenesis, and spine development will alter the development of hypothalamic circuits, which will in turn impair hypothalamic integration of signals reflecting states of nutrition and fat stores. Aim 1 will determine if TrkB-expressing neurons in the arcuate nucleus (ARC) respond to changes in feeding status and investigate if BDNF regulates axonal growth of these neurons using both in vivo and in vitro approaches. Aim 2 will investigate if BDNF differentially regulates the formation of excitatory and inhibitory synapses in ARC neurons expresing either neuropeptide Y or proopiomelanocortin using both immunohistochemistry against presynaptic markers and whole-cell patch-clamp recordings. Aim 3 will determine if TrkB in the dorsomedial hypothalamus (DMH) is required for the control of energy balance and if the number and shape of dendritic spines on TrkB-expressing DMH neurons are altered in mutant mice that lack local BDNF synthesis and develop severe obesity. Findings from this proposed project would provide insights into the mechanism by which BDNF regulates energy balance as well as the role of structural changes in hypothalamic neural circuits in the development of obesity. PUBLIC HEALTH RELEVANCE: Obesity has become a leading health issue in this country due to its high prevalence and associated disorders. Despite the enormous economic cost of obesity, no effective treatments for obesity are currently available. Continuing research efforts to understand the molecular, cellular, and physiological processes regulating energy homeostasis are needed in order to develop effective and safe anti-obesity therapies.